CN101031285A - Composition containing fine particles and process for producing the same - Google Patents
Composition containing fine particles and process for producing the same Download PDFInfo
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- CN101031285A CN101031285A CNA2005800332595A CN200580033259A CN101031285A CN 101031285 A CN101031285 A CN 101031285A CN A2005800332595 A CNA2005800332595 A CN A2005800332595A CN 200580033259 A CN200580033259 A CN 200580033259A CN 101031285 A CN101031285 A CN 101031285A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Abstract
The present invention provides a composition containing fine particles of a hardly-soluble drug which is stable and is not affected by storage environment conditions, as well as a manufacturing method therefor. The present invention provides a fine particle-containing composition containing fine particles of the hardly-soluble drug, a surfactant and a cyclic oligosaccharide, wherein an average particle size of the fine particles is at least 50 nm but not more than 1000 nm. The present invention also provides a method for manufacturing a fine particle-containing composition, comprising (I) a mixing step in which the hardly-soluble drug, the surfactant and a poor solvent are mixed to obtain a liquid mixture, (II) a pulverization step in which the liquid mixture is pulverized with a wet disperser to obtain a dispersion of fine particles, (III) an addition step in which the cyclic oligosaccharide is added to the dispersion of fine particles, and (IV) a drying step in which the dispersion of fine particles containing the cyclic oligosaccharide is dried.
Description
Technical field
The present invention relates to a kind of composition and method of making the same that contains the insoluble drug microgranule.
Background technology
Because the dissolubility of insoluble drug in water is low, therefore be difficult to usually carry out preparationization as injection.In addition, when being engaged in the solid preparation, there are difficult points such as difficult stripping from solid preparation, the easy reduction of bioavailability.Therefore, attempt addressing the above problem by the dispersibility that makes the insoluble drug miniaturization, improve in the water.For example, the known injection that contains the anticarcinogen that is adjusted to nano-scale etc. shows hypotoxicity and high bioavailability.
The preparation method of insoluble drug microgranule is so that the case of wet attrition of water or organic solvent is a main flow, and, use surface modifiers such as surfactant during case of wet attrition.Reason is, makes the particle surface of insoluble drug have electrostatic or spatial repulsion by surfactant etc., can prevent the coagulation of particle in the liquid, is easy to keep the uniformly dispersed of suspension.And, when handling the suspension contain by the insoluble drug microgranule of surfactant-dispersed,, can and use the clouding point regulator for the function of damaging surface activating agent not with high temperature such as autoclaves.The combination that for example discloses isotonic agents such as ionic surfactant and mannitol, dextrose or sodium chloride (for example, referring to United States Patent (USP) the 5th, 298, No. 262 description), or the combination of nonionic surfactant and clouding point regulators such as glycols, ethanol or hydroxypropyl cyclodextrin (for example, referring to United States Patent (USP) the 5th, 346, No. 702 description).And, by using Pu Luluonike nonionic surfactant and polymer substances such as (Pluronic), the particle size of insoluble drug is limited to 150～350nm, also can obtain stable injection (for example, showing the 2002-538199 communique) even in autoclave etc., carry out high-temperature process referring to the spy.
On the other hand, disclose the compositions for the insoluble drug microgranule that obtains containing nano-scale, the suspension that the preparation method that adopts above-mentioned insoluble drug microgranule is obtained carries out exsiccant method by lyophilization, spray drying method or fluidized bed pelletize again.For example, a kind of freeze-drying preparation for injection is disclosed, this freeze-drying preparation for injection is to make by the preparation method of using lyophilization, contain as the sucrose of antifreezing agent and as the polyvinyl pyrrolidone of surface stabilizer as must composition (for example, referring to United States Patent (USP) the 5th, 302, No. 401 description).
But, use the solid composite of sugar alcohol such as mannitol or nonionic surfactant, can not obtain the lyophilized preparation of target.In addition,, disclose after preparation contains the suspension of HER2 inhibiting substances of hydroxypropyl cellulose and NaTDC, carried out spray-dired method (for example, opening the 2003-26676 communique) referring to the spy as the preparation method of using spray drying method.Drug particle in the suspension and the drug particle after the powdered are about 900nm as a result, do not change.And, as adopting the fluidized bed process for granulating, disclose a kind of at the surface modifier that uses macromolecular compound, surfactant or saccharide as drug particle, after preparing the suspension of the microgranule that contains 500～1500nm, this suspension pelletize is made the method (for example, opening the 2004-175795 communique) of solid composite by fluidized bed referring to the spy.
Summary of the invention
As mentioned above, it is the injection that contains medium such as water of purpose that the micronize technology of insoluble drug is mainly used in the dispersion stabilization that improves microgranule in the liquid, fully studies as yet about the application in solid preparation commonly used.Though prior art has been considered the storage stability of microgranule in liquid, still unexposed preparation method or the compositions that is conceived to the insoluble drug microgranule of the stability of microgranule in solid composite.Particularly, in the preparation method of existing insoluble drug microgranule, surfactant is to be used for the surface modification of insoluble drug, to improve the necessary composition at the water dispersible of liquid.But under the state in being scattered in solid composite, surfactant is not to be neccessary composition, heat bonding problem between the crystalline growth of worrying meeting generation promotion drug microparticles or the microgranule.
On the other hand, medicine requires to guarantee qualities such as chemistry, physical stability in its process of circulation.Its reason is that the chemical change or the physical change of preserving process Chinese medicine or compositions not only make medicine suitably not use, and may the patient's that take medicine safety be exerted an influence.Certainly, in the compositions that contains the insoluble drug microgranule, the variation of its particle size also can make the water dispersible of drug microparticles reduce, and bioavailability is exerted an influence.
The inventor etc. study above-mentioned problem, found that following method, promptly, the suspension of the insoluble drug microgranule that case of wet attrition obtains in the solution that contains insoluble drug and surfactant (below, be called particle dispersion liquid) in, by adding the ring-type oligosaccharide again, though obtain in solidification processes such as drying process and at coagulation again or the crystalline growth of under high temperature or high humidity, preserving, also can suppress the insoluble drug microgranule behind the solid state, keep the compositions of the size of drug microparticles.In addition, also find following microgranule stabilization method, promptly, particle dispersion liquid drying that will the insoluble drug that case of wet attrition obtains in the solution that contains insoluble drug and surfactant, obtain containing the compositions of microgranule, by in said composition, further mixing the bad solution of ring-type oligosaccharide and a spot of insoluble drug, make the insoluble drug microgranule stabilisation in the compositions that contains microgranule, thereby finish the present invention.Foregoing invention discloses by ring-type oligosaccharide enclose surfactant and has suppressed surfactant in the solid-state composition to the influence of insoluble drug microgranule, the novel method of dissolving or heat bonding etc. for example.
That is, the invention provides:
1, a kind of compositions that contains microgranule, described compositions contains insoluble drug microgranule, surfactant and ring-type oligosaccharide, it is characterized by, and the mean diameter of described microgranule is below the above 1000nm of 50nm.
2, as the preceding paragraph 1 described compositions that contains microgranule, described compositions is by comprising the preparation method preparation of following operation, and promptly (I) mixes insoluble drug, surfactant and poor solvent, obtains the mixed processes of mixed liquor; (II) use the wet type dispersion machine with above-mentioned mixed liquor miniaturization, obtain the miniaturization operation of particle dispersion liquid; (III) in above-mentioned particle dispersion liquid, add the interpolation operation of ring-type oligosaccharide and (IV) drying contain the drying process of the particle dispersion liquid of above-mentioned ring-type oligosaccharide.
3, as the preceding paragraph 1 described compositions that contains microgranule, described compositions is by comprising the preparation method preparation of following operation, and promptly (I) mixes insoluble drug, surfactant and poor solvent and ring-type oligosaccharide, obtains the mixed processes of mixed liquor; (II) use the wet type dispersion machine with above-mentioned mixed liquor miniaturization, the miniaturization operation that obtains particle dispersion liquid reaches (III) drying process of dry above-mentioned particle dispersion liquid.
4, as the preceding paragraph 1 described compositions that contains microgranule, described compositions is by comprising the preparation method preparation of following operation, and promptly (I) mixes insoluble drug, surfactant and first poor solvent, obtains the mixed processes of mixed liquor; (II) use the wet type dispersion machine with above-mentioned mixed liquor miniaturization, obtain the miniaturization operation of particle dispersion liquid; (III) obtain first drying process of first mixture by the above-mentioned particle dispersion liquid of drying; (IV) in above-mentioned first mixture, add the interpolation operation that the ring-type oligosaccharide and second poor solvent obtain second mixture; (V) second drying process of dry above-mentioned second mixture.
5, as each described compositions that contains microgranule in the preceding paragraph 2 to 4, wherein, mixing is dissolved in the insoluble drug solution that good solvent obtains with insoluble drug in described mixed processes.
6,, wherein, also be included in the enrichment process that described drying process or described first drying process concentrate described particle dispersion liquid before or contain the particle dispersion liquid of described ring-type oligosaccharide as each described compositions that contains microgranule in the preceding paragraph 2 to 5.
7, as each described compositions that contains microgranule in the preceding paragraph 2 to 6, wherein, described drying process or described first drying process are the drying processes that adopts spray drying method.
8, as each described compositions that contains microgranule in the preceding paragraph 2 to 7, wherein, described wet type dispersion machine is a homogenizer.
9, as each described compositions that contains microgranule in the preceding paragraph 1 to 8, it is characterized by the described surfactant of described ring-type oligosaccharide enclose.
10, as each described compositions that contains microgranule in the preceding paragraph 1 to 9, wherein, described ring-type oligosaccharide is a cyclodextrin.
11, as each described compositions that contains microgranule in the preceding paragraph 1 to 10, wherein, described surfactant is to have the surfactant of carbon number at the hydrocarbon chain more than 4.
12, as each described compositions that contains microgranule in the preceding paragraph 1 to 11, wherein, with respect to the described compositions that contains microgranule of 100 mass parts, insoluble drug is 0.1～40 mass parts.
13, a kind of solid pharmaceutical composition contains each described compositions that contains microgranule in the preceding paragraph 1 to 13.
14, as preceding paragraph 13 described solid pharmaceutical compositions, wherein, described solid pharmaceutical composition is selected from tablet, granule, capsule and dry syrup.
15, a kind of preparation of compositions method that contains microgranule, described preparation method comprises following operation, promptly (I) mixes insoluble drug, surfactant and poor solvent, obtains the mixed processes of mixed liquor; (II) use the wet type dispersion machine with above-mentioned mixed liquor miniaturization, obtain the miniaturization operation of particle dispersion liquid; (III) the interpolation operation of interpolation ring-type oligosaccharide reaches (IV) the dry above-mentioned drying process that contains the particle dispersion liquid of ring-type oligosaccharide in above-mentioned particle dispersion liquid.
16, a kind of preparation of compositions method that contains microgranule, described preparation method comprises following operation, promptly (I) mixes insoluble drug, surfactant, poor solvent and ring-type oligosaccharide, obtains the mixed processes of mixed liquor; (II) use the wet type dispersion machine with above-mentioned mixed liquor miniaturization, obtain the miniaturization operation of particle dispersion liquid; (III) drying process of dry above-mentioned particle dispersion liquid.
17, a kind of preparation of compositions method that contains microgranule, described preparation method comprises following operation, promptly (I) mixes insoluble drug, surfactant and first poor solvent, obtains the mixed processes of mixed liquor; (II) use the wet type dispersion machine with above-mentioned mixed liquor miniaturization, obtain the miniaturization operation of particle dispersion liquid; (III) obtain first drying process of first mixture by the above-mentioned particle dispersion liquid of drying; (IV) in above-mentioned first mixture, add the interpolation operation that the ring-type oligosaccharide and second poor solvent obtain second mixture; (V) second drying process of dry above-mentioned second mixture.
18, as each described preparation of compositions method that contains microgranule in the preceding paragraph 15 to 17, wherein, in described mixed processes, mixing is dissolved in the insoluble drug solution that good solvent obtains with insoluble drug.
19, as each described preparation of compositions method that contains microgranule in the preceding paragraph 15 to 18, wherein, also be included in the enrichment process that described drying process or described first drying process concentrate described particle dispersion liquid before or contain the particle dispersion liquid of described ring-type oligosaccharide.
20, as each described preparation of compositions method that contains microgranule in the preceding paragraph 15 to 19, wherein, described drying process or described first drying process are the drying processes that adopts spray drying method.
21, as each described preparation of compositions method that contains microgranule in the preceding paragraph 15 to 20, wherein, described wet type dispersion machine is a homogenizer.
22, as each described preparation of compositions method that contains microgranule in the preceding paragraph 15 to 21, it is characterized by, at the described surfactant of ring-type oligosaccharide enclose described in the described interpolation operation.
23, as each described preparation of compositions method that contains microgranule in the preceding paragraph 15 to 22, wherein, described ring-type oligosaccharide is a cyclodextrin.
24, as each described preparation of compositions method that contains microgranule in the preceding paragraph 15 to 23, wherein, described surfactant is to have the surfactant of carbon number at the hydrocarbon chain more than 4.
25, as each described preparation of compositions method that contains microgranule in the preceding paragraph 15 to 24, wherein, with respect to the described compositions that contains microgranule of 100 mass parts, insoluble drug is 0.1～40 mass parts.
According to the present invention; in the case of wet attrition by using surfactant with insoluble drug in the micronized technology; by further use ring-type oligosaccharide; even contain in the drying process of suspension of insoluble drug microgranule and in the dried compositions in drying, also can suppress this insoluble drug microgranule through the time coagulation and crystalline growth.In addition, the present invention can provide a kind of compositions that contains microgranule, but the insoluble drug microgranule is not stably existed by the influence physical property of preservation environment such as temperature or humidity in said composition.Therefore, the present invention can be coupled to the insoluble drug microgranule simply as the commonly used tablet of oral formulations and capsule or can redispersionization in the time spent blending type dry syrup etc. in the water.And, the present invention can provide a kind of medical composition, and described compositions is carried out oral administration owing to keeping the size ground of insoluble drug as microgranule, therefore can promote the absorption of insoluble drug, improve the minimizing of bioavailability or realization medication amount etc., the compliance excellence of taking medicine.In addition, the medical composition that contains the compositions of microgranule or contain it of the present invention, because excellent storage stability, therefore easy premixing raw material or medicine as medicine transports circulation, can extensively popularize.
Description of drawings
[Fig. 1] is the flow chart of the preparation section of first embodiment among expression the present invention.
[Fig. 2] is the flow chart of the preparation section of second embodiment among expression the present invention.
[Fig. 3] is the flow chart of the preparation section of expression the 3rd embodiment of the present invention.
[Fig. 4] is the flow chart of the preparation section of expression the 4th embodiment of the present invention.
[Fig. 5] is illustrated in the dispersion liquid that contains glibenclamide (glibenclamide) microgranule the figure that the microgranule mean diameter with respect to α-CD/SDS mol ratio changes.
The figure of the dissolubility of glibenclamide when [Fig. 6] is expression α-CD and SDS coexistence.
[Fig. 7] is the figure of stripping curve that expression contains the tablet of glibenclamide microgranule.
[Fig. 8] is that expression contains the figure of the tablet of glibenclamide microgranule at the stripping curve of preserving the test front and back.
The specific embodiment
Following embodiment is to be used to illustrate example of the present invention, the present invention only is not defined in the meaning of this embodiment.The present invention only otherwise break away from its main idea can be according to multiple scheme implementation.
The compositions that contains microgranule of the present invention represents that the insoluble drug microgranule is present in the compositions in the solid phase.The compositions that contains microgranule of the present invention contains insoluble drug, surfactant and ring-type oligosaccharide, and the microparticulate of insoluble drug is in said composition.In addition, said composition also can contain additives such as other saccharides or polymer substance in case of necessity.The compositions that contains microgranule of the present invention can be by after further adding the ring-type oligosaccharide in the particle dispersion liquid that contains the insoluble drug microgranule, make it dry and make, described insoluble drug microgranule is to obtain by case of wet attrition in the solution that contains insoluble drug and surfactant.In addition, the ring-type oligosaccharide also can mix use with insoluble drug and surfactant before case of wet attrition.In addition, the also insoluble drug particle dispersion liquid drying that case of wet attrition in the solution that contains insoluble drug and surfactant can be obtained, obtain containing the compositions of insoluble drug microgranule and surfactant, in the compositions that obtains, further add ring-type oligosaccharide and a spot of poor solvent, carry out combination drying, obtain the compositions that contains microgranule of the present invention.In above-mentioned preparation method, form inclusion body by ring-type oligosaccharide and part or all of surfactant, at drying process or contain the physical and chemical stability that helps the insoluble drug microgranule in the preservation process of compositions of microgranule.
So-called microgranule of the present invention, the particle of the nano-scale of expression mean diameter below 1 μ m also claims so-called nanoparticle, its mean diameter can use light scattering method to measure.For example, the compositions that will contain the insoluble drug microgranule is mixed with poor solvent, make this insoluble drug microparticulate, dilute in case of necessity, can adopt the instrument of the particle diameter that can measure nano-scale, for example dynamic light scattering photometer DLS-7000 of Otsuka Electronics Co., Ltd. or laser Z potentiometer ELS-8000 etc. measure.Equally, the insoluble drug microgranule in the particle dispersion liquid also can suitably adopt the poor solvent dilution of insoluble drug to measure.The mean diameter of insoluble drug microgranule adopts light scattering method that solid dispersion is distributed to when measuring in the water among the present invention, is limited to 1000nm on it, is preferably 900nm, more preferably 800nm.The lower limit of mean diameter does not have special qualification, can be 50nm, is preferably 100nm, more preferably 200nm.So the mean diameter of insoluble drug microgranule of the present invention is 50nm～1000nm, preferred 100nm～900nm, more preferably 200nm～800nm.
Among the present invention, so-called medicine contains curative or diagnosis medicine.Curative can be for containing the medicine from the medicine of biology such as synthetic compound, protein and peptide, and the diagnosis medicine is Baryan or other diagnostic medicines.Medicine is preferably slightly solubility, can be dispersed at least a liquid medium.Herein, so-called slightly solubility, as the dissolubility of medicine in solvent, the state of expression " indissoluble " in terms of record in Japanese Pharmacopoeia 14 editions (below, Japanese Pharmacopoeia) or the American Pharmacopeia 24 editions (following USP), " utmost point indissoluble " or " almost insoluble ".Particularly, in the Japanese Pharmacopoeia, dissolubility is meant under medicine is solid-state situation, after becoming powder, add in the solvent, when 20 ± 5 ℃ of strong joltings in per 5 minutes mixed in 30 seconds, the dissolution degree in 30 minutes, the required water yield not enough 1000mL more than 100mL of so-called " indissoluble " expression dissolving 1g medicine.In addition, the required water yield not enough 10000mL more than 1000mL of so-called " utmost point indissoluble " expression dissolving 1g medicine, so-called " almost insoluble " represents that the required water yield of dissolving 1g medicine is more than 10000mL.Among the present invention, insoluble drug preferably is the medicine of " utmost point indissoluble " or " almost insoluble " to the dissolubility of water, that is, and and the required medicine of the water yield more than 1000mL of dissolving 1g medicine.Insoluble drug preferably is the medicine of " almost insoluble " to the dissolubility of water, that is, and and the required medicine of the water yield more than 10000mL of dissolving 1g medicine.
Insoluble drug of the present invention does not have special qualification, it for example is steroid class medicine, enzyme inhibitor, analgesics, antifungal, cancer therapeutic agent, antiemetic, analgesics, circulatory system drug, antiinflammatory, anthelmintic, anti-arrhythmic agents, antibiotic (comprising penicillin), anticoagulant, antidepressant, antidiabetic, Anti-epileptics, the dementia agent, hydryllin, hypotensive agent, antimuscarinic agent, anti-mycobacteria medicine, anti-malignant tumor agent, immunosuppressant, antithyroid drug, antiviral agent, anxiety tranquilizer (somnifacient and neuroleptics), astringent, the beta-2 adrenoceptor blocker, Blood Preparations and substitute agent, cardiac tonic, contrast agent, corticosteroid, antitussive (removing expectorant agent and mucolytic agent), diagnostic agent, the diagnosis contrast agent, diuretic, dopamine agonist (anti-parkinson agent), hemorrhage, immunizing agent, lipid regulating agent, muscle relaxant, prostaglandin, the radioactivity pharmaceuticals, hormone preparation, anti-allergic agent, stimulant and anoretic, sympathomimetic, thyroid, vasodilations etc. can be selected from multiple medicine.Above-mentioned insoluble drug can be for a kind of or share two or more.
Containing the use level of insoluble drug in the compositions of microgranule, with respect to the compositions that contains microgranule of 100 mass parts, is 0.1～40 mass parts, preferred 0.5～35 mass parts, more preferably 1～30 mass parts, more preferably 1～25 mass parts.
Surfactant of the present invention can be when making the insoluble drug miniaturization and insoluble drug together use, have the effect that makes the insoluble drug miniaturization effectively.Perhaps, when being distributed to the compositions that contains microgranule of the present invention in the water equal solvent once more, has the homodisperse effect of the insoluble drug of making microgranule.Therefore, get final product so long as have the material of surface activity ability, do not have special qualification, preferably can improve the high HLB surface activity of the water dispersible of insoluble drug microgranule, for example HLB more than 8, preferred HLB is more than 10, more preferably HLB is at the surfactant more than 12.
In addition, surfactant of the present invention does not have special qualification so long as at least a portion of this surfactant can be got final product by the material of cyclodextrin inclusion compound.For example for having the surfactant of hydrocarbon chain, hydrocarbon chain can be straight chain, side chain, ring-type, does not have special qualification, for example can enumerate nonionic surfactant, ionic surfactant, natural surfactant with hydrocarbon chain.Surfactant of the present invention is preferably the carbon number of hydrocarbon chain more than 4, more preferably more than 6, more preferably at the surfactant more than 8, and the carbon number of preferred especially hydrocarbon chain is at the surfactant more than 10.The example of concrete surfactant is as follows, but is not limited thereto.As nonionic surfactant, can enumerate glyceryl monostearate, sorbitan fatty ester, single myristic acid ten glyceride, polyglycerol fatty acid glyceride (Nikko Chemicals Co., Ltd) such as mono laurate six glyceride or glyceryl monooleate, sucrose fatty acid ester (SANLING changes into food Co., Ltd.), castor oil derivatives (CO series (registered trade mark), Nikko Chemicals Co., Ltd), polyoxyethylene hydrogenated Oleum Ricini (for example, HCO series (registered trade mark), Nikko Chemicals Co., Ltd), Oleum Cocois mono fatty acid polyoxyethylene sorbitan esters, polysorbate 80 (trade name Tween80 etc.), polysorbate 20 polyoxyethylene sorbitan fatty acid esters such as (trade name Tween20 etc.), polidocanol (Lauromacrogol) or polyoxyethylene (20) cetyl ether, polyoxyethylene alkyl ethers (Nikko Chemicals Co., Ltd) such as polyoxyethylene (15) oleyl ether, polyoxyethylene polyoxy-propylene (Nikko Chemicals Co., Ltd) such as polyoxyethylene (20) polyoxypropylene (4) cetyl ether, polyethylene glycol mono stearate, cithrol such as polyglycol distearate or polyethylene glycol monooleate (Nikko Chemicals Co., Ltd).As ionic surfactant, can enumerate acyl-lactates such as fatty acid soaps, stearyl sodium lactate or stearyl calcium lactate, sodium lauryl sulphate alkyl sulfates such as (Wako Pure Chemical Industries, Ltd.) salt, alkylphosphonic, benzalkonium chloride, hexadecylpyridinium chloride etc.As natural surfactant, can enumerate cholates such as soybean lecithin (True-Lecithin industry), hydrogenation soybean phospholipid (True-Lecithin Industrial Co., Ltd) or Ovum Gallus domesticus Flavus lecithin (Q.P. Co., Ltd.), LYSOLECITHIN SUNLECITHIN A (Kyowa Hakkokogyo Co., Ltd), hydroxide lecithin lecithin such as (Nikko Chemicals Co., Ltd) class, sodium cholate or NaTDC.Above-mentioned surfactant can use separately, also can share more than 2 kinds.Preferred alkyl sulfuric acid, sucrose fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyglycerol fatty acid glyceride, more preferably alkyl sulfate salt, sucrose fatty acid ester, polysorbate 80, polysorbate 20.
The ring-type oligosaccharide that uses among the present invention is so long as have the material of the performance of enclose surfactant and get final product, then there is not special qualification, for example be ring-type oligosaccharide that constitutes by 4～12 glucose units or the few lactose of ring-type that constitutes by the lactose unit, preferred alpha-cyclodextrin (japanese food processing Co., Ltd.), beta-schardinger dextrin-(japanese food processing Co., Ltd.), gamma-cyclodextrin (japanese food processing Co., Ltd.) or, ring-type tetrose (Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo), more preferably alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin.Above-mentioned ring-type oligosaccharide may be used alone, two or more kinds can also be used in combination.
The relative quantity of insoluble drug, surfactant and ring-type oligosaccharide in the compositions that contains microgranule of the present invention does not have special qualification, in addition, can contain the composition outside the mentioned component yet.For example, with respect to 1 mass parts insoluble drug, the match ratio of ring-type oligosaccharide is 0.5～1000 mass parts in containing the compositions of microgranule, is preferably 1～500 mass parts, more preferably is 2～200 mass parts, more preferably 3～100 mass parts.In addition, contain in the compositions of microgranule with respect to 1 mass parts insoluble drug, the match ratio of surfactant is 0.1～10 mass parts, is preferably 0.2～5 mass parts, more preferably is 0.2～2 mass parts, more preferably 0.4～1 mass parts.
The preparation of compositions method that contains microgranule of the present invention comprises following operation,, insoluble drug is made the miniaturization operation of microgranule under the condition that surfactant exists, the interpolation operation of adding the ring-type oligosaccharide, the drying process of dry particles dispersion liquid that is.By comprising the interpolation operation of adding the ring-type oligosaccharide, the surfactant that enclose uses in the miniaturization operation, promptly free surfactant or be adsorbed on the surfactant on insoluble drug surface.The result can suppress because the coagulation of the insoluble drug microgranule that the existence of surfactant causes or the crystalline growth of insoluble drug in drying process or in the dried compositions.So, illustrate the preparation of compositions method that contains microgranule of the present invention by following embodiment.
(first embodiment of the present invention)
Fig. 1 is the procedure declaration figure about first embodiment of the preparation of compositions method that contains microgranule of the present invention.Being characterized as of the present embodiment after with the insoluble drug miniaturization, added the ring-type oligosaccharide in particle dispersion liquid.Promptly (I) mixes insoluble drug, surfactant and poor solvent in mixed processes, obtains mixed liquor.(II) with above-mentioned mixed liquor miniaturization, obtains particle dispersion liquid with the wet type dispersion machine in the miniaturization operation then; Add in the operation in (III), add the ring-type oligosaccharide in above-mentioned particle dispersion liquid, mix, then (IV) passes through first drying process, and drying contains the particle dispersion liquid of above-mentioned ring-type oligosaccharide, can access the compositions that contains microgranule of the present invention.
(second embodiment of the present invention)
Fig. 2 is the procedure declaration figure about second embodiment of the preparation of compositions method that contains microgranule of the present invention.Being characterized as under the coexistence of ring-type oligosaccharide, of the present embodiment with the insoluble drug miniaturization.Promptly (I) mixes insoluble drug, surfactant, ring-type oligosaccharide and poor solvent in mixed processes, obtains mixed liquor; (II) by the miniaturization operation then, will contain the mixed liquor miniaturization of above-mentioned ring-type oligosaccharide with the wet type dispersion machine, obtains the dispersion liquid of the microgranule of above-mentioned insoluble drug.(III) passes through drying process again, and drying contains the particle dispersion liquid of above-mentioned ring-type oligosaccharide, can access the compositions that contains microgranule of the present invention.
(the 3rd embodiment of the present invention)
Fig. 3 is the procedure declaration figure about the 3rd embodiment of the preparation of compositions method that contains microgranule of the present invention.Being characterized as of the present embodiment after obtaining containing the compositions of insoluble drug microgranule and surfactant, added ring-type oligosaccharide and poor solvent and mixed.Promptly (I) mixes insoluble drug, surfactant and first poor solvent in mixed processes, obtains mixed liquor.(II) with above-mentioned mixed liquor miniaturization, obtains particle dispersion liquid with the wet type dispersion machine by the miniaturization operation then.(III) by first drying process again, and dry above-mentioned particle dispersion liquid obtains containing above-mentioned insoluble drug microgranule and above-mentioned surfactant mixtures (below, be called first mixture).Then (IV) adds the ring-type oligosaccharide and second poor solvent by adding operation in first mixture, mixes, and obtains mixture (below, be called second mixture).Next, in order to remove second poor solvent, (V) as second drying process, dry second mixture can obtain containing the compositions of microgranule.Herein, first poor solvent can be identical with second poor solvent, also can be different.In addition, obtain the operation of first mixture or second mixture, can use other saccharide or polymer substance etc.Need to prove that second drying process can be removed second poor solvent and get final product, its method does not have special qualification.
(the 4th embodiment of the present invention)
The dispersion technology that miniaturization operation of the present invention adopts has used wet type dispersion machine and surfactants such as homogenizer or mill, the method for preferred further combination partial crystallization technology.For example, can make up with first embodiment as shown in Figure 4.That is, be included in insoluble drug is mixed the preparation method that with the wet type dispersion machine above-mentioned mixed liquor miniaturization is obtained the miniaturization operation of particle dispersion liquid after the mixed processes that obtains mixed liquor with surfactant, poor solvent with the form of the insoluble drug solution that is dissolved in good solvent and obtains.Wishing that surfactant or ring-type oligosaccharide dissolve in advance, are scattered in insoluble drug solution or the poor solvent herein, mixes.And, in order from above-mentioned mixed liquor, to remove good solvent, or, preferably before drying process, add enrichment process in order further to remove poor solvent.Particularly,, can use ultrafiltration or dialysis to remove good solvent or poor solvent, concentrate particle dispersion liquid, afterwards, can access the compositions that contains microgranule of the present invention by drying process for the particle dispersion liquid that contains the ring-type oligosaccharide.Need to prove, identical with first embodiment, also comprise above-mentioned partial crystallization technology or enrichment process by making the second or the 3rd embodiment, can access finer microgranule, can improve effect of the present invention.
In addition, as the preparation of compositions method that contains microgranule of the present invention, can be with first, second or the 4th embodiment and the combination of the 3rd embodiment.For example, obtain the compositions that contains microgranule of the present invention by first embodiment after, may further include and add second drying process that ring-type oligosaccharide and second poor solvent carry out blended interpolation operation and be used to remove second poor solvent.Perhaps, also can be included in to contain and add the drying process that ring-type oligosaccharide and poor solvent carry out blended interpolation operation and be used to remove the poor solvent of interpolation in the compositions that adopts insoluble drug microgranule that additive method obtains in advance and surfactant.Embodiment of the present invention not only are defined in this.
Mixed processes of the present invention is to mix insoluble drug, surfactant and poor solvent before miniaturization operation of the present invention, mixes ring-type oligosaccharide or other additives more as required, obtains the operation of mixed liquor.In order to obtain microgranule efficiently in ensuing miniaturization operation, the expectation mixed liquor is the mixed uniformly state of each composition.Therefore, the various operations on insoluble drug particle, broken medicament powder, modification medicament powder surface in mixed processes, have been carried out being used to disperse.For example, when operations such as the stirring of mixed liquor, the pulverizing of medicament powder, except using propeller(type)stirrer (agitator mixer) or homodisperse machine (Mizuho Industrial Co., Ltd), homomixer (Mizuho Industrial Co., Ltd), homogeneous phase spraying machine (Tokushu Kika Kogyo K.K), pressurization mulser, colloid mill (Tokushu Kika Kogyo K.K), jet pulverizer (tremble Co., Ltd. of this ironworker institute), disintegrating machine etc., can suitably use the wet type dispersion machine that uses in the miniaturization operation.For example, insoluble drug is directly used after the coarse pulverization in jet pulverizer or disintegrating machine with the powder body form, in homomixer, mix with surfactant or poor solvent etc.In addition, after also can insoluble drug and surfactant be mediated or mixing, add solvent, in wet type dispersion machine of the present invention, carry out miniaturization with disintegrating machine or grinder.
In micronize operation of the present invention, as the dispersion technology of insoluble drug, adopt surfactant, and share with the wet type dispersion machine.That is, at the mixed liquor of mixed processes gained of the present invention, promptly contain in the solution of insoluble drug and surfactant, with the insoluble drug miniaturization, obtain containing the operation of the particle dispersion liquid of insoluble drug microgranule with the wet type dispersion machine.Surfactant concentrations in mixed liquor during miniaturization does not have special qualification, is generally 0.01～5w/v%, is preferably 0.1～4w/v%, more preferably 0.3～3w/v%.
When further using the partial crystallization technology in the miniaturization operation of the present invention, in mixed processes of the present invention,, can separate out the microgranule of insoluble drug by insoluble drug being dissolved in insoluble drug solution and the blended mixed processes of poor solvent that good solvent obtains.At this moment, the surfactant that uses in the mixed processes can add in poor solvent or the good solvent any or add in the two and use.In addition, when adopting the partial crystallization technology, preferably behind mixed processes, use the wet type dispersion machine immediately.That is, behind the mixed processes, usually in 5 minutes, preferably in 3 minutes, more preferably in 1 minute, use the wet type dispersion machine to carry out miniaturization, modulate the dispersion liquid of insoluble drug microgranule thus.
Good solvent among the present invention is the solvent that dissolves insoluble drug fully, there is not special qualification, for example can enumerate lower alcohols such as methanol, ethanol, normal propyl alcohol, isopropyl alcohol, ketones such as acetone, methyl ethyl ketone, the mixed solvent of acetonitrile, diox, methyl ether, chloroform or above-mentioned solvent.In addition, poor solvent of the present invention is the solvent that dissolves insoluble drug hardly, does not have special qualification, for example can enumerate the acid water of water, the various acid of adding, the alkaline water of the various alkali of adding.Need to prove, when using the partial crystallization technology, poor solvent be preferably can with the above-mentioned blended solvent of drug solution that is dissolved in good solvent.When the insoluble drug solution that is dissolved in good solvent mixes with poor solvent,, there is not special qualification as long as mixed proportion can make medicine separate out, the amount of good solvent is with respect to poor solvent, be generally 0.001～50v/v%, be preferably 0.01～10v/v%, more preferably 0.01～5v/v%.
The wet type dispersion machine that uses in the miniaturization operation of the present invention as long as have the ability of insoluble drug being made microgranule of the present invention, does not have special restriction.As grinder, compression, the shear action that can produce by the rotation by pearl, ball, ring or roller etc. are carried out miniaturization.For example can enumerate trade name Dyno-mill (W.A.Bachofen society, Switzerland), ball mill (Fritsch society, Germany), trade name Micros (Nara Machinery Co., Ltd.), trade name Super Clean Mill (nara machinery is made institute), trade name Drais Bead Mill (De Laishi company, the U.S.) etc.As homogenizer,, its structure there is not special qualification so long as can provide the device of the shearing force that can make the miniaturization of insoluble drug microgranule, impulsive force, cavitation erosion power, high speed flow velocity, ultrasound wave etc. to get final product.For example can enumerate and treatment fluid is impacted mutually or make its high-pressure homogenizer that passes through small hole, utilize the shearing force that the microgap by rotor, stator or screen cloth etc. produces or the high speed rotating type homogenizer of cavitation erosion power, or homogenizer such as ultrasonic homogenizer.As high-pressure homogenizer, can enumerate trade name Nanomizer (the industrial Co., Ltd. of Jitian's machinery), trade name Microfluidizer (MFI society, the U.S.), Piston gap homogenizer (trade name EmulsiFlex-C160, Avestin Inc. Canada), APV formula homogenizer (Invensys Systems Co., Ltd.), trade name Clear-SS5 (MTechnique Co., Ltd.), Niro Soavi society homogenizer (with flourish business Co., Ltd.), trade name Ultimizer (the Sugino Machine of Co., Ltd.) etc., do not have special qualification.High speed rotating type homogenizer, can enumerate high-performance dispersion emulsifying machine (trade name Clearmix, M.Technique Co., Ltd.), trade name Polytron homogenizer (KINEMATICA society), trade name Hiscotron (icrotechNichion of M Co., Ltd.) etc.As ultrasonic homogenizer, can enumerate efficient supersonic homogenizer (Japanese Siber Hegner) etc.The preferred homogenizer of wet type dispersion machine of the present invention, more preferably high-pressure homogenizer.
When using high-pressure homogenizer as wet type dispersion machine of the present invention, because the pressure during miniaturization depends on device capability, so there is not special qualification, when not using other dispersion technology, be generally 14000psi～60000psi, be preferably 20000psi～60000psi, more preferably 30000psi～60000psi.When share with partial crystallization technology etc., the pressure when being the miniaturization of high-pressure homogenizer unexpectedly is lower pressure, is generally 500～40000psi, is preferably 1000～30000psi, more preferably 3000～30000psi.In addition, temperature of liquid when the present invention uses high-pressure homogenizer to carry out miniaturization does not have special qualification, is generally the temperature that insoluble drug is not dissolved in solvent fully, is limited to down the temperature of the uncured or thicknessization of solvent, particularly is 1～40 ℃.Be preferably 1～30 ℃ especially.And the miniaturization that utilizes high-pressure homogenizer to carry out does not have special qualification to number of pass times, can carry out continuously with tandem, obtains the target microgranule.
When using high speed rotating type homogenizer as wet type dispersion machine of the present invention, the number of revolutions during miniaturization also depends on device, usually more than 12000rpm, preferably more than the 15000rpm, more preferably more than 18000rpm.In addition, the temperature of processed liquid does not have special qualification in this processing, is generally the temperature that insoluble drug is not dissolved in solvent fully, is limited to down the temperature of the uncured or thicknessization of solvent, particularly is 1～40 ℃.Be preferably 1～30 ℃ especially.
When using grinder as wet type dispersion machine of the present invention, after the method for preparation particle dispersion liquid is included in the solution that contains surfactant insoluble drug is carried out bulk processing, the operation of in the presence of crushing medium, grinding.
Interpolation operation of the present invention is carried out blended operation for adding the ring-type oligosaccharide, and its purpose is for making ring-type oligosaccharide enclose surfactant.At this moment, can make in case of necessity poor solvent that the ring-type oligosaccharide is dissolved or dispersed in insoluble drug for example water add after medium.In addition, mixing herein is so long as can make surfactant get final product with the mixing that the ring-type oligosaccharide contacts, and its mixed method does not have special qualification.For example can utilize stirring operation or device in the mixed processes.Need to prove,, when in first mixture that contains insoluble drug microgranule and surfactant, adding the ring-type oligosaccharide, add second poor solvent and mix as the 3rd embodiment.Second poor solvent can be identical with first poor solvent that is used for mixed processes, also can be other poor solvent.In addition, adding the addition that second poor solvent carries out the blended method or second poor solvent does not have special qualification, can or be moist powder body for liquid, pasty state by adding second mixture that second poor solvent obtains.Preferably in the interpolation operation of the 3rd embodiment, in first mixture that obtains by first drying process, add second poor solvent as the binder solution in the so-called wet type pelletize with the ring-type oligosaccharide.By dry this pelletize thing, can obtain the compositions that contains microgranule of the present invention.
Drying process of the present invention is the operation of the dry particles dispersion liquid or second mixture, can remove the good solvent or the poor solvent that wherein contain.Above-mentioned drying process for example can use known method such as spray drying method, fluidized bed comminution granulation, lyophilization or shelf type seasoning separately or be used in combination several different methods, but is not limited thereto.Spray drying method makes its drying can obtain containing the compositions of microgranule with sprayings such as spray dryer particle dispersion liquid of the present invention.Inflow air themperature during spray drying usually 80 ℃～more than 200 ℃, preferably at 90 ℃～180 ℃, more preferably 100 ℃～160 ℃.In addition, the solid component concentration of the particle dispersion liquid during spray drying is 0.5～30% for example, is preferably 1～20%, more preferably 3～15%.Herein, so-called solid component concentration is represented in the dispersion liquid in each drying process nonvolatile composition, is the total concentration of insoluble drug, surfactant, ring-type oligosaccharide, other excipient etc.In addition, the fluidized bed comminution granulation carries out pelletize by atomized spray particle dispersion liquid of the present invention in the powder of lactose or starch etc., obtains containing the compositions of microgranule.Lyophilization is add isotonic agent such as saccharide etc. in particle dispersion liquid after, to use freeze dryer, freezes to-20 ℃～-60 ℃ usually and removes to desolvate and make its drying, obtains containing the compositions of microgranule.The shelf type seasoning is that particle dispersion liquid directly or is again made after the excipient adsorption solvent, usually 50 ℃～80 ℃ dry down, obtain containing the compositions of microgranule.First drying process in drying process of the present invention or the 3rd embodiment, preferably spray drying method, lyophilization or fluidized bed comminution granulation, more preferably spray drying method.After the spray drying, can adopt fluidized bed equipment or shelf type drying again, further carry out redrying.In addition, second drying process in the 3rd embodiment can promptly, according to the character of second mixture, be selected drying means according to the addition of second poor solvent.For example, if second mixture is liquid, then can use the method identical with the drying means of particle dispersion liquid.During for the wet type powder body, can use the fluidized bed comminution granulation.Need to prove, in the drying process of the present invention, also can and with the method for absorption such as silicon dioxide etc., can also use the method solidification beyond the said method.
In the drying process of the present invention, can be engaged in additives such as necessary excipient of the powdered of utilizing in the known method or binding agent.But,, there is no need to add the above above-mentioned additive of necessary amount owing to, can realize the physically stableization of insoluble drug microgranule by adding the ring-type oligosaccharide.Therefore, owing to can obtain being combined with the compositions of the high-load insoluble drug microgranule also higher than the insoluble drug concentration in the final medicine preparation, so can be used in polytype solid pharmaceutical composition.
The compositions that contains microgranule of the present invention can by in oral, per rectum, non-oral (intravenous, intramuscular or subcutaneous), the capsule, in the transvaginal, intraperitoneal, part or oral cavity or nasal cavity give and the human or animal.
Use the compositions that contains microgranule of the present invention, can further be mixed with the medical composition that is used for various administering modes.As medical composition of the present invention, can orally give and tablet, powder, granula subtilis, granule, capsule, pill, dry syrup, dragee, liquor, suspension, Emulsion, elixir, syrup, dragee etc., in addition can non-oral giving and inhalant, suppository, injection, ointment, patch, paste, eye ointment, eye drop, nasal drop, ear drop, lotion etc.At this moment, the compositions that contains microgranule also can be used the kind or the different compositions that contains microgranule more than 2 kinds of concentration of insoluble drug.
Medical composition of the present invention can directly use the compositions that contains microgranule, the additive that can use the pharmacology to allow.During for solid pharmaceutical composition, can use excipient commonly used, binding agent, disintegrating agent, lubricant, coloring agent, coating materials etc.Then, cooperate above-mentioned additive, by known method, that is, and can be with mixing, pelletize, compression, beat operative combination such as sheet, capsule filling, the preparation solid pharmaceutical composition.
Injection can be as required adds cosolvent, isotonic agent, stabilization agent, painlessization agent, buffer agent, outstanding turbidization agent, antioxidant etc. in the compositions that contains microgranule of the present invention, carry out preparationization according to common method.During injection, also can be lyophilized formulations.Because injection is sterile preparation, therefore high pressure heat sterilization more than 8 minutes under 121 ℃ condition for example.In addition, injection can be to vein, Intradermal, subcutaneous, intramuscular administration.Injection of the present invention is preferably the injection of time spent blending type.The injection of time spent blending type can directly use the compositions that contains microgranule of the present invention, or also can add isotonic agents such as sucrose, glucose, D-mannitol, sodium chloride.For example, in the particle dispersion liquid of insoluble drug, add above-mentioned isotonic agent as required, obtain containing the compositions of microgranule, the compositions that contains microgranule that obtains can be made the injection of time spent blending type by the lyophilization drying.
External agent of the present invention adds base material, emulsifying agent, thickening agent, preservative agent, stabilizing agent etc. in the compositions that contains microgranule of the present invention, according to common method, can be prepared into ointment, cream, suppository, patch, lotion etc.Perhaps, make the lotion of time spent blending type in the same manner with injection.As the base raw material that uses, can use normally used various raw materials in pharmaceuticals, medicine part outer article, the cosmetics etc., for example can enumerate raw materials such as vegetable and animals oils, mineral oil, ester oil, wax class, higher alcohols, fatty acid, silicone oil, surfactant, phospholipid, alcohols, polyalcohols, water soluble polymer class, clay mineral class, distilled water, can add pH regulator agent, antioxidant, chelating agen, preservative agent, coloring agent, spice etc. in case of necessity.
Concrete example as the additive that uses in the medical composition of the present invention, for example, excipient is D-mannitol, lactose (comprising Lactis Anhydrous), white sugar (comprising castor sugar), sodium bicarbonate, corn starch, potato starch, wheaten starch, rice starch, part alphalysed starch, crystalline cellulose, light silicon dioxide, calcium phosphate dibasic anhydrous, calcium monohydrogenphosphate, tertiary calcium phosphate, precipitated calcium carbonate, calcium silicates etc.; Binding agent can be enumerated polyvinylpyrrolidone, dextrin, hydroxypropyl cellulose, hypromellose, methylcellulose, polyvinyl alcohol, sodium carboxymethyl cellulose, alphalysed starch, sodium alginate, amylopectin, arabic gum powder etc., but is not limited to above-mentioned substance.As lubricant, hydrogenated oil and fat, castor oil hydrogenated, stearic acid, magnesium stearate, calcium stearate, mountain Yu acid glyceride, sodium stearyl fumarate etc. are arranged; As disintegrating agent, can cooperate low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl starch sodium, crospolyvinylpyrrolidone etc., but be not limited to above-mentioned substance.And, as coating materials, can enumerate hydroxypropyl cellulose, hypromellose, ethyl cellulose, Hydroxypropyl methyl cellulose phtalate, carboxylic first and second celluloses, sodium carboxymethyl cellulose, carboxymethyl cellulose potassium, cellulose acetate, cellulose derivatives such as Cellacefate, ethyl acrylate methylmethacrylate copolymer dispersion liquid, amino alkyl methacrylate copolymer E, EudragitRS PO EUDRAGIT RSPO eudragit RS-100 eudragit RS-PO, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, 2-methyl-5-vinylpyrine acrylic acid methyl ester. methacrylic acid copolymer, acrylic polymers such as dimethylaminoethyl methacrylate methylmethacrylate copolymer, polyvinylpyrrolidone, polyvinyl acetal diethyl amino yl acetate, polyvinyl alcohol, polyoxyethylene polyoxypropylene glycol, synthetic high polymer materials such as Polyethylene Glycol, amylopectin, polysaccharide or gelatin such as chitosan, succinic acid gelatin (succinated gelatin), arabic gum, natural family macromolecule material such as lac etc.As plasticizer, can enumerate dioctyl adipate, triethyl citrate, glycerol triacetate, glycerol, concentrated glycerin, propylene glycol etc.; As suspension or emulsifying agent, can enumerate lecithin, sucrose fatty acid ester, polyglyceryl fatty acid ester, polyoxyethylene hydrogenated Oleum Ricini, polysorbate, poloxalkol etc.; As fumet, can enumerate menthol, Oleum menthae, Fructus Citri Limoniae oil, orange oil etc.; As antioxidant, can enumerate sodium ascorbate, L-cysteine, sodium sulfite, natural Vitamin E etc.; As the sugar-coat agent, can enumerate white sugar, lactose, starch syrup, precipitated calcium carbonate, arabic gum, Brazil wax, lac, Cera Flava, Polyethylene Glycol, ethyl cellulose, methylcellulose, polyvinylpyrrolidone etc.; As anti-blushing agent, can enumerate magnesium silicate, light silicon dioxide, hydrogenated oil and fat, stearic acid, magnesium stearate, paraffin, Oleum Ricini, Polyethylene Glycol, vinylacetate resin, cellulose acetate-phthalate, polyvinyl acetal diethyl amino yl acetate, lac etc.; As fluidizer, can enumerate aqueous silicon dioxide, light silicon dioxide, heavy silicon dioxide, crystalline cellulose, synthetic aluminium silicate, aluminum magnesium hydroxide, inclined to one side aluminosilicate magnesium (magnesium metasilicate aluminate), stearic acid, calcium stearate, magnesium stearate, tertiary calcium phosphate, Pulvis Talci, corn starch etc.; In addition, as coloring agent, can enumerate tar class pigment, yellow iron sesquioxide, iron sesquioxide (colcother), Black Rouge, titanium oxide, zinc oxide, Pulvis Talci, Rhizoma Curcumae Longae extract, caramel, carotene liquid, beta-carotene, copper pheophytin, sodium copper chlorophyllin, riboflavin, white carbon black, medicinal charcoal etc. such as edible yellow No. 4, edible yellow No. 5, edible red No. 2, edible red No. 102, edible blue No. 1, edible blue No. 2 (indigo carmines), edible yellow No. 4 aluminum color lakes.As solvent, can enumerate water, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, Benzoinum acid benzyl ester, propylene glycol, 1,3-butanediol, dimethyl formamide, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Fructus Maydis oil, olive oil, Oleum Ricini, Oleum sesami, glycerol, Polyethylene Glycol etc., but be not limited to above-mentioned substance.
The compositions that contains microgranule of the present invention particularly can be prepared in accordance with the following methods.To the 10.5mg/mL of 38mL sodium lauryl sulphate (Wako Pure Chemical Industries, Ltd.; hereinafter to be referred as SDS) add in the aqueous solution 2mL 200mg/mL glibenclamide (glibenclamide) (4-[2-(5-chloro-2-anisoyl amino) ethyl] (N-cyclohexyl carboxyamide base) benzene-sulfonamide; water-soluble hardly; Wako Pure Chemical Industries, Ltd.; hereinafter to be referred as glibenclamide) dimethyl sulfoxide (Wako Pure Chemical Industries, Ltd.; hereinafter to be referred as DMSO) solution; after the stirring; join nanometer ultramicron processing machine Nanomizer (industrial Co., Ltd. of Jitian's machinery rapidly; hereinafter to be referred as Nanomizer) in; handled 10 minutes, and obtained particle dispersion liquid thus.By the SDS aqueous solution that uses 10mg/mL above-mentioned dispersion liquid is carried out dialysis treatment, remove DMSO, obtain spissated particle dispersion liquid.Adding the 1350mg alpha-cyclodextrin among this particle dispersion liquid of every 7.5mL A (japanese food processing Co., Ltd., mixes hereinafter to be referred as α-CD), 12.5mL distilled water.By using rotary dryer Pulvis Mini-Spray GB22 (big and science Co., Ltd., hereinafter to be referred as S.D.-GB22) this solution of spray drying, obtain solidified compositions that contains microgranule.The compositions that contains microgranule that will be by the method preparation is carried out pelletize, is played sheet or capsule filling with after excipient, disintegrating agent, lubricant etc. mix, and can be used as granule, tablet or capsule and use.
Below, enumerate embodiment, the present invention is described in further detail, but the present invention is not limited to these embodiment.In addition, the additive in the composite medicine uses the material or the reagent of official standards such as meeting Japanese Pharmacopoeia, medicine additive standard 2003, the outer drug standard 1997 of Japanese Pharmacopoeia.
Embodiment
(embodiment 1)
In the 10.5mg/mLSDS of 38mL aqueous solution, after the DMSO solution stirring of the 200mg/mL glibenclamide of adding 2mL, join rapidly among the Nanomizer, handle obtaining particle dispersion liquid in 10 minutes.Use the 10mg/mLSDS aqueous solution that this dispersion liquid is carried out dialysis treatment and remove DMSO, obtain spissated dispersion liquid (below, be called dispersion liquid A).Add 1350mg α-CD, 12.2mL distilled water among every 7.5mL dispersion liquid A, mix (concentration of glibenclamide, SDS and α-CD in the solid component concentration 7.5%=dispersion liquid).Using S.D.-GB22 is under 115 ℃ flowing into air themperature, and this solution is carried out spray drying, obtains containing the compositions (air quantity: 0.5m of microgranule
3/ min, atomizing air: 1kgf/cm
2, liquid supply speed: 7mL/min).Spray drying obtains containing the compositions of microgranule.The result obtains containing in the compositions that per 100 mass parts contain microgranule the compositions that contains microgranule of 5 mass parts glibenclamide, 5 mass parts SDS, 90 mass parts α-CD.
(embodiment 2～embodiment 3)
In the preparation method of embodiment 1, with beta-schardinger dextrin-(japanese food processing Co., Ltd., hereinafter to be referred as β-CD) or gamma-cyclodextrin (japanese food processing Co., Ltd., hereinafter to be referred as γ-CD) replace α-CD to prepare, obtain respectively containing β-CD the compositions that contains microgranule (embodiment 2), contain the compositions that contains microgranule (embodiment 3) of γ-CD.
(comparative example 1～6, reference examples 1)
Saccharide shown in the use table 1 obtains containing the compositions of microgranule.The compositions that contains microgranule that contains lactose of comparative example 1 is that benchmark is prepared with embodiment 1 described method, in the spray drying temperature is to obtain under 175 ℃ the condition.The compositions that contains microgranule that contains D-mannitol of comparative example 2 makes according to embodiment 1 described method.In addition, the compositions that contains microgranule that contains erithritol, sucrose, trehalose is prepared as follows, promptly, after in the 5.1mg/mLSDS of 39mL aqueous solution, adding the DMSO solution stirring of 200mg/mL glibenclamide of 1mL, join rapidly among the Nanomizer, handle obtaining particle dispersion liquid in 10 minutes.Use the 5mg/mLSDS aqueous solution that this dispersion liquid is carried out dialysis treatment and remove DMSO, obtain spissated dispersion liquid (below, be called dispersion liquid B).Add each saccharide of 1350mg, 5mL distilled water among every 15mL dispersion liquid B, mix (solid component concentration 7.5%).Use S.D.-GB22 flowing under the condition that air themperature is (comparative example 3, comparative example 5, reference examples 1) or 175 ℃ under 115 ℃ the condition (comparative example 4), this solution is carried out spray drying, obtain containing the compositions (air quantity: 0.5m of microgranule
3/ min, atomizing air: 1kgf/cm
2, liquid supply speed: 7mL/min).Its result is identical with embodiment 1, obtains the compositions that contains microgranule that compositions that per 100 mass parts contain microgranule contains 5 mass parts glibenclamide, 5 mass parts SDS, 90 mass parts saccharides.And, use sodium chloride to replace erithritol, attempting preparing, but microparticle agglutination and precipitation in the dispersion liquid can not be carried out spray drying.In addition, reference examples 1 is for not adding the system of cyclodextrin or saccharide, at 115 ℃ of following spray drying dispersion liquid B (solid component concentration 1%) (air quantity: 0.5m
3/ min, atomizing air: 1kgf/cm
2, liquid supply speed: 7mL/min), do not contained the compositions that contains microgranule (containing 50 mass parts glibenclamide, 50 mass parts SDS in the 100 mass parts compositionss) of cyclodextrin.
(test example 1)
(preserving test)
The compositions that contains microgranule of the foregoing description or comparative example preparation is filled into respectively in the vial, and this vial is not added a cover directly to be put in the preservation storehouse that environmental condition is 60 ℃, 75% (relative humiditys) and was preserved for 1 week.Measure the particle diameter of microgranule in the compositions that respectively contains microgranule before and after preserving.
(assay method of mean diameter)
The compositions that contains microgranule added in the distilled water stir, obtain the solution of insoluble drug microparticulate.The mensuration of this moment is 0.25mg/mL with the glibenclamide concentration in the dispersion liquid.Use ELS-8000 (Otsuka Electronics Co., Ltd.) carry out the mensuration of particle diameter by dynamic light scattering method, adopt the accumulation diameter as mean diameter.According to measured value, obtain mean diameter after the preservation with respect to the rate of change of initial stage mean diameter.
The result is as shown in table 1.The mean diameter of the glibenclamide microgranule among the dispersion liquid A is 205.8nm.In addition, among the dispersion liquid B, mean diameter is 198.6nm.Surprisingly, almost do not have to take place to be kept in the environment of high humility after the change of size that causes by spray drying and the powdered even contain the compositions that contains microgranule of cyclodextrin, almost do not occur yet the glibenclamide microgranule through the time change of size.
Saccharide in contrast, after spray drying, with the system that cooperates cyclodextrin much at one, but the mean diameter after the powdered increases, even the D-mannitol of change minimum also increases to more than 1.4 times.In addition, do not cooperate the reference examples of cyclodextrin or saccharide to become more than the 1000nm by the spray drying mean diameter.And mean diameter also increases in preserving test.Therefore, can judge when the ring-type oligosaccharide helps to be suppressed at the spray drying of drying process or the coagulation or the crystalline growth of insoluble drug microgranule during the preservation after the preparation.Particularly, can confirm to compare, have the effect that can suppress the change of size of solidification microgranule, i.e. coagulation under the solidification state and crystalline growth significantly with other saccharides.
[table 1]
| Saccharide | Mean diameter (nm) | Rate of change (%) | ||
| Initial stage | After the preservation | |||
| Embodiment 1 | α-CD | 222.0 | 234.2 | 5 |
| Embodiment | ||||
| 2 | β-CD | 243.4 | 221.5 | -9％ |
| Embodiment 3 | γ-CD | 224.8 | 231.0 | 3％ |
| Comparative example 1 | Lactose | 210.7 | 885.5 | 320％ |
| Comparative example 2 | D-mannitol | 219.8 | 310.5 | 41％ |
| Comparative example 3 | Erithritol | 218.8 | 2230.1 | 919％ |
| Comparative example 4 | Sucrose | 209.3 | 1224.2 | 485％ |
| Comparative example 5 | Trehalose | 203.6 | 874.3 | 329％ |
| Comparative example 6 | Sodium chloride | Coagulation sedimentation | - | |
| Reference examples 1 | Do not add | 1257.6 | 3915.4 | 211％ |
Match ratio: glibenclamide/SDS/ saccharide=5/5/90
Reference examples 1: glibenclamide/SDS/ saccharide=50/50/0
(embodiment 4)
According to embodiment 1 described method preparation dispersion liquid A.Add 225mg α-CD among this dispersion liquid of every 7.5mL A and mix (solid component concentration 5%).Using S.D.-GB22 is under 115 ℃ the condition flowing into air themperature, and above-mentioned solution is carried out spray drying, obtains containing the compositions (air quantity: 0.5m of microgranule
3/ min, atomizing air: 1kgf/cm
2, liquid supply speed: 7mL/min).The result obtains containing in the compositions that per 100 mass parts contain microgranule the compositions that contains microgranule of 20 mass parts glibenclamide, 20 mass parts SDS, 60 mass parts α-CD.
(comparative example 7)
In the method for embodiment 4, use D-mannitol to replace α-CD to prepare.In test example 1, D-mannitol can suppress the variation of microgranule mean diameter in the saccharide except that the CD class.
(test example 2)
Preserve test in the same manner with test example 1, measure the mean diameter of insoluble drug microgranule.Its result is as shown in table 2.Contain in the compositions of microgranule in the solidification that contains high concentration medicine, the ring-type oligosaccharide also have inhibition by through the time coagulation and the crystalline growth change of size that causes effect.Need to prove that the mean diameter of the microgranule of the dispersion liquid A of embodiment 4 is 214.8nm.
[table 2]
| Saccharide | Mean diameter (nm) | Rate of change (%) | ||
| Initial stage | After the | |||
| Embodiment | ||||
| 4 | α-CD | 251.8 | 524.4 | 108％ |
| Comparative example 7 | D-mannitol | 233.6 | 1095.5 | 369％ |
Match ratio: glibenclamide/SDS/ saccharide=20/20/60
(embodiment 5)
Adding 1275mg lactose, 75mg α-CD, 12.5mL distilled water mix (solid component concentration 7.5%) among every 7.5mL embodiment 4 described dispersion liquid A.Using S.D.-GB22, is the above-mentioned solution of spray drying under 175 ℃ the condition flowing into air themperature, obtains solidified compositions (air quantity: 0.5m that contains microgranule
3/ min, atomizing air: 1kgf/cm
2, liquid supply speed: 7mL/min).The result obtains containing in the compositions that per 100 mass parts contain microgranule the compositions that contains microgranule of 5 mass parts glibenclamide, 5 mass parts SDS, 5 mass parts α-CD, 85 quality powder lactose.
(embodiment 6)
Adding 1200mg lactose, 150mg α-CD, 12.5mL distilled water mix (solid component concentration 7.5%) among every 7.5mL embodiment 4 described dispersion liquid A.By using the above-mentioned solution of S.D.-GB22 spray drying, obtain solidified compositions that contains microgranule.The result obtains the compositions that contains microgranule that compositions that per 100 mass parts contain microgranule contains 5 mass parts glibenclamide, 5 mass parts SDS, 10 mass parts α-CD, 80 quality powder lactose.
(test example 3)
Preserve test in the same manner and measure mean diameter with test example 1.Its result is as shown in table 3.With the mixed system of other excipient of lactose and so in, the ring-type oligosaccharide also have inhibition by through the time coagulation and the crystalline growth change of size that causes effect.
[table 3]
| Match ratio | Mean diameter (nm) | Rate of change (%) | ||
| Initial stage | After the preservation | |||
| Comparative example 1 | 5/5/0/90 | 210.7 | 885.5 | 320％ |
| Embodiment 5 | 5/5/5/85 | 218.5 | 532.5 | 144％ |
| Embodiment 6 | 5/5/10/80 | 227.2 | 301.4 | 33％ |
Match ratio: glibenclamide/SDS/ α-CD/ lactose
(embodiment 7)
In the 20mg/mLSDS of 40mL aqueous solution, add after the 2000mg glibenclamide stirs, join rapidly among the Nanomizer, handle obtaining particle dispersion liquid (below, be called dispersion liquid C) in 10 minutes.Every 2mL dispersion liquid C adds 1860mg α-CD, the 28mL distilled water mixes (solid component concentration 6.7%).Using S.D.-GB22 is under 115 ℃ the condition flowing into air themperature, and above-mentioned solution is carried out spray drying, obtains containing the compositions (air quantity: 0.5m of microgranule
3/ min, atomizing air: 1kgf/cm
2, liquid supply speed: 7mL/min).The result obtains the compositions that contains microgranule that compositions that per 100 mass parts contain microgranule contains 5 mass parts glibenclamide, 2 mass parts SDS, 93 mass parts α-CD.
(embodiment 8)
Add 860mg α-CD, 13mL distilled water among every 2mL embodiment 7 described dispersion liquid C, mix (solid component concentration 6.7%).Using S.D.-GB22 is under 115 ℃ the condition flowing into air themperature, and above-mentioned solution is carried out spray drying, obtains containing the compositions (air quantity: 0.5m of microgranule
3/ min, atomizing air: 1kgf/cm
2, liquid supply speed: 7mL/min).The result obtains the compositions that contains microgranule that compositions that per 100 mass parts contain microgranule contains 10 mass parts glibenclamide, 4 mass parts SDS, 86 mass parts α-CD.
(embodiment 9)
Add 360mg α-CD, 5.5mL distilled water among every 2mL embodiment 7 described dispersion liquid C, mix (solid component concentration 6.7%).Using S.D.-GB22 is under 115 ℃ the condition flowing into air themperature, and above-mentioned solution is carried out spray drying, obtains containing the compositions (air quantity: 0.5m of microgranule
3/ min, atomizing air: 1kgf/cm
2, liquid supply speed: 7mL/min).The result obtains the compositions that contains microgranule that compositions that per 100 mass parts contain microgranule contains 20 mass parts glibenclamide, 8 mass parts SDS, 72 mass parts α-CD.
(embodiment 10)
Add 110mg α-CD, 1.75mL distilled water among every 2mL embodiment 7 described dispersion liquid C, mix (solid component concentration 6.7%).Using S.D.-GB22 is under 115 ℃ the condition flowing into air themperature, and above-mentioned solution is carried out spray drying, obtains containing the compositions (air quantity: 0.5m of microgranule
3/ min, atomizing air: 1kgf/cm
2, liquid supply speed: 7mL/min).The result obtains containing in the compositions that per 100 mass parts contain microgranule the compositions that contains microgranule of 40 mass parts glibenclamide, 16 mass parts SDS, 44 mass parts α-CD.
(reference examples 2)
Using S.D.-GB22, is under 115 ℃ the condition flowing into air themperature, and embodiment 7 described dispersion liquid C (solid component concentration 7.0%) are directly carried out spray drying, obtains containing the compositions (air quantity: 0.5m of microgranule
3/ min, atomizing air: 1kgf/cm
2, liquid supply speed: 7mL/min).
(test example 4)
Preserve the test and the mensuration of mean diameter in the same manner with test example 1.The result is as shown in table 4.Though not shown in the table, the mean diameter of microgranule is 675.6nm among the dispersion liquid C.Can confirm, compare,, also can suppress the change of size that causes by spray drying even the embodiment drug level of cooperation CD is 40% high concentration with the reference examples 2 that does not cooperate CD.What particularly point out is, when drug level is 5～20% concentration, contain medicine by solidified compositions that contains microgranule in, the ring-type oligosaccharide also have inhibition by through the time coagulation and the crystalline growth change of size that causes effect.In addition, according to this test as can be known, identical with the compositions that contains microgranule of using dispersion liquid A or dispersion liquid B to prepare, when using dispersion liquid C, though the mean diameter of drug microparticles becomes greatly slightly, but still can obtain the stable compositions that contains microgranule, wherein, above-mentioned dispersion liquid A or dispersion liquid B are dissolved in good solvent with insoluble drug and make in mixed processes, above-mentioned dispersion liquid C is not dissolved in insoluble drug good solvent promptly to be mixed and implement miniaturization and make.
[table 4]
| Contain ratio | Mean diameter (nm) | Rate of change (%) | ||
| Initial stage | After the preservation | |||
| Embodiment 7 | 5/2/93 | 554.5 | 620.3 | 12 |
| Embodiment | ||||
| 8 | 10/4/86 | 562.0 | 692.8 | 23％ |
| Embodiment 9 | 20/8/72 | 564.2 | 633.5 | 12 |
| Embodiment | ||||
| 10 | 40/16/44 | 576.2 | 1325.2 | 130％ |
| Reference examples 2 | 71/29/0 | 624.5 | 7142.6 | 1044％ |
Contain ratio: glibenclamide/SDS/ α-CD
(embodiment 11)
The compositions that contains microgranule, 400mg lactose, 15mg hydroxypropyl cellulose (HPC-L, Japanese Cao Da) and the 10% α-CD aqueous solution 55 μ L of 100mg embodiment 1 gained are mixed in mortar.This mixture after under 60 ℃ dry 2 hours, is carried out pelletize by the mandatory 16 purposes sieve that sieved, obtain containing the granule of glibenclamide microgranule and α-CD.
(embodiment 12)
The compositions that contains microgranule, 400mg lactose, 11.5mgHPC-L and the 7%HPC-L aqueous solution 54 μ L of 100mg embodiment 2 gained are mixed in mortar.This mixture after under 60 ℃ dry 2 hours, is carried out pelletize by the mandatory 16 purpose screen clothes that sieved, obtain containing the granule of glibenclamide microgranule and β-CD.
(embodiment 13)
The compositions that contains microgranule, 310mg lactose, 90mg α-CD, 15mgHPC-L and the 10% α-CD aqueous solution 55 μ L of 100mg comparative example 1 gained are mixed in mortar.This mixture after under 60 ℃ dry 2 hours, is carried out pelletize by the mandatory 16 purpose screen clothes that sieved, obtain containing the microgranule of glibenclamide and the granule of α-CD.
(comparative example 8)
The compositions that contains microgranule, 400mg lactose, 15mgHPC-L and the 50 μ L distilled water of 100mg comparative example 1 gained are mixed in mortar.This mixture after under 60 ℃ dry 2 hours, is carried out pelletize by the mandatory 16 purpose screen clothes that sieved, obtain the granule that contains glibenclamide microgranule and lactose, do not contain the CD class.
(comparative example 9)
The compositions that contains microgranule, 400mg lactose, 11.5mgHPC-L and the 7%HPC-L aqueous solution 54 μ L of 100mg comparative example 1 gained are mixed in mortar.This mixture after under 60 ℃ dry 2 hours, is carried out pelletize by the mandatory 16 purpose screen clothes that sieved, obtain the granule that contains glibenclamide microgranule and lactose, do not contain the CD class.
(test example 5)
Under the condition identical, preserve test with test example 1.Also measure mean diameter in the same manner with test example 1.The result is as shown in table 5.Its result shows, uses by solidified granule that contains the compositions preparation of microgranule, after implementing the pelletize operation, also can suppress the change of size that coagulation and crystalline growth by the insoluble drug microgranule cause.And, surprisingly, contain the embodiment 11-13 of ring-type oligosaccharide in the prescription, almost can suppress fully by through the time coagulation and the crystalline growth particle diameter that causes increase.Particularly embodiment 13, even can confirm to add the ring-type oligosaccharide in the pelletize stage, also can suppress effectively by through the time coagulation and the crystalline growth change of size that causes.Promptly, can confirm not only in the particle dispersion liquid before dry, to add under the situation of ring-type oligosaccharide, and under the situation that is to add in solidification mixture (first mixture of the 3rd embodiment etc.) dry back, the particle diameter of insoluble drug microgranule increases in the time of also preventing to preserve.This result confirms that the effect of ring-type oligosaccharide of the present invention has the effect different with the encloseization of so-called insoluble drug.
[table 5]
| Composition | Embodiment 11 | Embodiment 12 | Embodiment 13 | Comparative example 8 | Comparative example 9 | |
| Glibenclamide | 5 | 5 | 5 | 5 | 5 | |
| SDS | 5 | 5 | 5 | 5 | 5 | |
| HPC-L | 15 | 15.3 | 15 | 15 | 15.3 | |
| α-CD or β-GD | 95.5 | 90 | 95.5 | 0 | 0 | |
| Lactose | 400 | 400 | 400 | 490 | 490 | |
| Granule amounts to (mg) | 521 | 515 | 521 | 515 | 515 | |
| Mean diameter (nm) | Initial stage | 316.2 | 323.6 | 342.2 | 354.2 | 332.0 |
| After the preservation | 311.9 | 308.8 | 338.8 | 464.1 | 397.6 | |
| Rate of change (%) | -1％ | -5％ | -1％ | 31％ | 20％ | |
(reference examples 3)
With the DMSO solution 2mL of 200mg/mL glibenclamide join stir in the 38mL distilled water after, promptly drop among the Nanomizer, carry out Nanomizer and handle.But, under the preparation condition that does not use SDS, because the stream obturation of Nanomizer, therefore can not the preparation of nano suspension.The reference examples 2 of matching surface activating agent, can access the particle dispersion liquid and the dried compositions that contains microgranule that contain the following microgranule of 1000nm, can confirm that thus particularly the existence of surfactant is crucial when case of wet attrition in preparation method of the present invention.
(test example 6)
In order to confirm the influence of cyclodextrin, change the concentration ratio of SDS and cyclodextrin, preparation contains the dispersion liquid of glibenclamide microgranule in accordance with the following methods, relatively mean diameter.Measure mean diameter according to the method identical with test example 1.
(compound method)
After 38mL contains the DMSO solution 2mL that adds the 200mg/mL glibenclamide in the aqueous solution of 200mg SDS and 169mg α-CD and stirs, promptly drop among the Nanomizer, by handling the dispersion liquid that obtained containing microgranule in 10 minutes.The DMSO solution 2mL that adds equally the 200mg/mL glibenclamide in 38mL contains the aqueous solution of 337mg, 675mg, 1350mg, 2700mg α-CD respectively obtains containing the dispersion liquid of microgranule.
(result of the test)
Result of the test as shown in Figure 5.Its result can confirm, by improving the α-CD concentration with respect to SDS, is about 1: 1 in the mol ratio of SDS and α-CD～at 1: 2 o'clock when preparation contains the dispersion liquid of microgranule, and mean diameter sharply changes.This result represents that the surface activity ability of SDS reduces, and infers between SDS and α-CD to form inclusion body.Can confirm from The above results, in order to obtain the littler particle of mean diameter, preferably after the dispersion liquid miniaturization that will contain medicine and surfactant, by adding the superfluous surfactant that exists of cyclodextrin inclusion compound.Certainly, also can in the dispersion liquid that contains medicine and surfactant, add cyclodextrin in advance, thereby realize purpose of the present invention.
(test example 7)
In test example 6 hint by cyclodextrin and SDS with the surfactant enclose.Therefore, under the condition of both coexistences, carry out the solubility test test, encloseization is inquired into.
(test method)
Contain to 4ml and to add the 20mg glibenclamide in the aqueous solution of α-CD, SDS, at room temperature stir more than 3 days.With pore-size is after the Millex-HV filter (Millipore system) of 0.45 μ m filters above-mentioned solution, measures glibenclamide concentration in the filtrate with Unison UK-C18 post (Imtakt system) by HPLC.
(result of the test)
Fig. 6 represents with respect to the SDS concentration under various α-CD concentration, the dissolubility of glibenclamide.When α-CD was 0.0mM, with respect to SDS concentration, dissolubility also increased, but in the system of adding α-CD, with respect to SDS concentration, had the bending point of expression minimal solubility.When above-mentioned solubility curve figure occurring, represent that both form inclusion body.And the mol ratio that its bending point is equivalent to α-CD/SDS is 1～2, and is consistent with the result of Fig. 5.
(embodiment 14)
According to embodiment 1 described method preparation dispersion liquid A, adding 1350mg α-CD, 12.5mL distilled water mix among every 7.5mL dispersion liquid A.At this moment, the mean diameter of the microgranule in containing the dispersion liquid of drug microparticles is 222.8nm.Using S.D.-GB22 is under 175 ℃ the condition flowing into air themperature, and this solution is carried out spray drying, obtains containing the compositions (air quantity: 0.5m of microgranule
3/ min, atomizing air: 1kgf/cm
2, liquid supply speed: 7mL/min).Its result obtains containing in the compositions that per 100 mass parts contain microgranule the compositions that contains microgranule of 5 mass parts glibenclamide, 5 mass parts SDS, 90 mass parts α-CD.This mean diameter that contains the microgranule in the compositions of microgranule is 314.7nm (175 ℃).With the spray drying temperature is that the embodiment 1 of 115 ℃ (other conditions are identical) compares, and particle size increases slightly, can obtain containing the compositions that contains microgranule of the following minuteness particle of 1000nm.
(embodiment 15)
Behind embodiment 1 described method preparation dispersion liquid A, adding 1350mg β-CD, 92.5mL distilled water mix (solid component concentration 1.5%) among every 7.5mL dispersion liquid A.At this moment, in containing the dispersion liquid of drug microparticles, the mean diameter of microgranule is 222.8nm.Use S.D.-GB22 flowing into 115 ℃ of air themperatures, air quantity 0.5m
3/ min, atomizing air 1kgf/cm
2, liquid supply speed 7mL/min condition under, this solution is carried out spray drying, obtain containing the compositions of microgranule.Its result obtains containing in the compositions that per 100 mass parts contain microgranule the compositions that contains microgranule of 5 mass parts glibenclamide, 5 mass parts SDS, 90 mass parts β-CD.The mean diameter of the microgranule in this compositions is 407.9nm.With solid component concentration in the dispersion liquid that contains microgranule is that 7.5% embodiment 2 compares, and particle size increases slightly, can obtain containing the compositions that contains microgranule of the following minuteness particle of 1000nm.
(embodiment 16)
(2-(2 to add the 100mg mefenamic acid in the 2mg/mL of 40mL SDS aqueous solution, 3-3,5-dimethylphenyl amino) benzoic acid, the water-soluble hardly and pure medicine of light) stir after, drop into rapidly among the Nanomizer, handle 10min and obtain particle dispersion liquid (following, be called dispersion liquid X).At this moment, the mean diameter of the drug microparticles among the dispersion liquid Z is 609nm.Every 1mL dispersion liquid X adds 40mg α-CD and mixes (solid component concentration 4.4%).Using S.D.-GB22 is under 115 ℃ flowing into air themperature, and this solution is carried out spray drying, obtains containing the compositions (air quantity: 0.5m of microgranule
3/ min, atomizing air: 1kgf/cm
2, liquid supply speed: 7mL/min).Its result obtains containing in the compositions that per 100 mass parts contain microgranule the compositions that contains microgranule of 5.6 mass parts mefenamic acives, 4.5 mass parts SDS, 89.9 mass parts α-CD.
(comparative example 10)
Add 40mg D-mannitol among the dispersion liquid X of every 1mL embodiment 16 preparations, mix (solid component concentration 4.4%).Using S.D.-GB22 is under 115 ℃ the condition flowing into air themperature, and this solution is carried out spray drying, obtains containing the compositions (air quantity: 0.5m of microgranule
3/ min, atomizing air: 1kgf/cm
2, liquid supply speed: 7mL/min).Its result obtains containing in the compositions that per 100 mass parts contain microgranule the compositions that contains microgranule of 5.6 mass parts mefenamic acives, 4.5 mass parts SDS, 89.9 mass parts D-mannitol.
(embodiment 17)
In the 5mg/mL of 40mL SDS aqueous solution, add 100mg spironolactone (7 α-thioacetyl-3-oxo-17 α-pregnant-4-alkene-21,17 beta-butyrolactones, 7 α-acetylsulfanyl-3-oxo-17 α-pregn-4-ene-21,17 β-carbolactone, the water-soluble hardly and pure medicine of light) stir after, drop into rapidly among the Nanomizer, handle 10min and obtain particle dispersion liquid (following, be called dispersion liquid Y).At this moment, the mean diameter of the drug microparticles among the dispersion liquid Z is 562nm.Add 42.5mg α-CD among this dispersion liquid of every 1mL Y and mix (solid component concentration 5%).Using S.D.-GB22 is under 115 ℃ the condition flowing into air themperature, and above-mentioned solution is carried out spray drying, obtains containing the compositions (air quantity: 0.5m of microgranule
3/ min, atomizing air: 1kgf/cm
2, liquid supply speed: 7mL/min).Its result obtains containing in the compositions that per 100 mass parts contain microgranule the compositions that contains microgranule of 5 mass parts spironolactones, 10 mass parts SDS, 85 mass parts α-CD.
(test example 8)
Preserve the test and the mensuration of mean diameter in the same manner with test example 1.But the drug level that adopts when mean diameter is measured is 0.1mg/ml.The result is as shown in table 6.As known from Table 6, compare as the embodiment 16 and the comparative example 10 of surfactant as medicine, use SDS with using mefenamic acid, by cooperating α-CD, the particle diameter in the time of can suppressing significantly to preserve under high humility increases.In addition, though not shown in the table, use spironolactone to be 756.1nm as the initial stage particle diameter of embodiment 17 after solidification of surfactant, and the particle diameter after preserving become 826.9nm as medicine, SDS, rate of change is 9%, and almost not observing particle diameter increases.Even surprisingly above result shows the effect that the particle diameter of the α-CD that still can be inhibited increases in the combination of multiple medicine and surfactant.
[table 6]
| Saccharide | Mean diameter (nm) | Rate of change (%) | ||
| Initial stage | After the preservation | |||
| Embodiment 16 | α-CD | 664.3 | 735.3 | 11％ |
| Comparative example 10 | D-mannitol | 615.8 | 1341 | 118％ |
Match ratio: mefenamic acid/SDS/ saccharide=5.6/4.5/89.9
In the 4.2mg/mLSDS of 38mL aqueous solution, add the DMSO solution 2mL of 200mg/mL glibenclamide, after the stirring, join rapidly among the Nanomizer, handle 10min and obtain particle dispersion liquid.Use the 4mg/mLSDS aqueous solution that this dispersion liquid is carried out dialysis treatment and remove DMSO, obtain dispersion liquid (below, be called dispersion liquid D).At this moment, the mean diameter of the drug microparticles among the dispersion liquid Z is 207nm.Add 186mg α-CD, 1.67mL distilled water among every 1mL dispersion liquid D, mix (solid component concentration 7.5%).Using S.D.-GB22 is under 115 ℃ the condition flowing into air themperature, and this solution is carried out spray drying, obtains containing the compositions (air quantity: 0.5m of microgranule
3/ min, atomizing air: 1kgf/cm
2, liquid supply speed: 7mL/min).Spray drying obtains containing the compositions of microgranule.As mobile phase, use the ODS post to contain the containing ratio of glibenclamide in the compositions of microgranule by high performance liquid chromatography (detecting wavelength 230nm) mensuration 0.1N potassium dihydrogen phosphate aqueous solution/acetonitrile=9/11 mixed liquor, the result is 4.15wt%.With respect to the above-mentioned compositions that contains microgranule of 2318mg, add 5282mg D-mannitol, 1000mg corn starch, 500mg low-substituted hydroxypropyl cellulose, 300mg hydroxypropyl cellulose, an amount of distilled water, after in mortar, mixing, carry out heat drying with temperature chamber.With respect to the dried granule of 8554mg, adding 455mg low-substituted hydroxypropyl cellulose, 91mg magnesium stearate are mixed.Weigh the 130mg said mixture, beat sheet, obtain containing the tablet of the diameter 7mm of 1.25mg glibenclamide with AUTOGRAPHAG5000A (Shimadzu Seisakusho Ltd.).
(comparative example 11)
With respect to the 96.2mg glibenclamide, add 2571.3mg α-CD, 4894.0mg D-mannitol, 38.5mg SDS, 1000mg corn starch, 500mg low-substituted hydroxypropyl cellulose, 300mg hydroxypropyl cellulose, an amount of distilled water, after in mortar, mixing, carry out heat drying with temperature chamber.With respect to the dried granule of 8554mg, add 455mg low-substituted hydroxypropyl cellulose, the mixing of 91mg magnesium stearate.Weigh the 130mg said mixture, beat sheet, obtain containing the tablet of the diameter 7mm of 1.25mg glibenclamide with AUTOGRAPHAG5000A (Shimadzu Seisakusho Ltd.).
(test example 9)
Adopt embodiment 18, preserve the mensuration of test and mean diameter in the same manner with test example 1.Preservation condition is set at 60 ℃ of 75%RH, 1 week and 1 month in this test.In addition, because tablet contains insoluble additive, therefore after being the filter filtration of 5 μ m, the use pore-size measures mean diameter.Its result is that the mean diameter of glibenclamide microgranule is 360.3nm in the tablet after preparation has just finished, in addition, 1 week was 404.7nm after preservation, preserving back 1 month is 403.3nm, and with respect to the mean diameter at initial stage, the rate of change of the mean diameter after the preservation is 11～12%.Use the compositions that contains microgranule of the present invention, by the tablet that the compression forming working procedure processing forms, drug microparticles is stable.Can confirm that by this test microgranule of the present invention is stablized the influence of compression section, excipient or preservation condition when not prepared.
(test example 10)
Carry out dissolution test for embodiment 18 and comparative example 11.In addition, for embodiment 18, the sample that is used to test the preservation test of example 7 carries out dissolution test.Dissolution test makes water as experimental liquid according to the dissolution test method of the 14th edition Japanese Pharmacopoeia, at the blade revolution is to test under the condition of 50rpm.In addition, use Millipore society the PVDF filter (pore-size: 0.22 μ m) filter through the time sample liquid of gathering after, analyze by HPLC, calculate the glibenclamide concentration in the sample liquid of gathering, obtain dissolution rate.HPLC analyzes in mobile phase: under the condition of 0.1N potassium dihydrogen phosphate aqueous solution/acetonitrile=9/11 mixed liquor, detection wavelength: 230nm, use the ODS post to measure.Its result compares with the comparative example 12 of the medicine that cooperates not miniaturization, and the embodiment 19 that medicine cooperates as microgranule has the effect (referring to Fig. 7) of improving the medicine stripping.In addition, the stripping curve of embodiment 19 before and after preserving almost do not change (referring to Fig. 8).So, can confirm that the compositions that contains microgranule of the present invention can improve the stripping property of insoluble drug, and the stripping of medicine from preparation is stable, can be owing to preservation changes.
Utilizability on the industry
The present invention makes in the micronized technology of insoluble drug by the case of wet attrition of using surfactant; by further use ring-type oligosaccharides; contain in the operation of suspension of insoluble drug particulate and in the dried composition in drying, can both suppress the insoluble drug particulate through the time aggegation and crystalline growth. In addition, the present invention can provide a kind of fine-grained composition that contains, and the insoluble drug particulate in the said composition is not stably existed by impact, the physical property of the preservation environment such as temperature or humidity. So the present invention can be coupled to the insoluble drug particulate simply as in the widely used tablet of oral formulations and the capsule or can be in the water again in decentralized time spent blending type dry syrup etc. And, the invention provides a kind of medical composition, in this medical composition insoluble drug kept particle size directly oral to, therefore can promote the absorption of insoluble drug, improve bioavilability, or realize the minimizing of medication amount, the biddability of taking medicine excellence. In addition, the medical composition that contains fine-grained composition or contain said composition of the present invention, because therefore excellent storage stability is easy to premixed raw material or medicine conveying circulation as medicine, can extensive use.
Claims (25)
1, a kind of compositions that contains microgranule, described compositions contains insoluble drug microgranule, surfactant and ring-type oligosaccharide, it is characterized by, and the mean diameter of described microgranule is below the above 1000nm of 50nm.
2, the compositions that contains microgranule as claimed in claim 1, described compositions is prepared by the preparation method that comprises following operation, and promptly (I) mixes insoluble drug, surfactant and poor solvent, obtains the mixed processes of mixed liquor; (II) use the wet type dispersion machine with described mixed liquor miniaturization, obtain the miniaturization operation of particle dispersion liquid; (III) in described particle dispersion liquid, add the interpolation operation of ring-type oligosaccharide and (IV) drying contain the drying process of the particle dispersion liquid of described ring-type oligosaccharide.
3, the compositions that contains microgranule as claimed in claim 1, described compositions is prepared by the preparation method that comprises following operation, and promptly (I) mixes insoluble drug, surfactant, poor solvent and ring-type oligosaccharide, obtains the mixed processes of mixed liquor; (II) use the wet type dispersion machine with described mixed liquor miniaturization, the miniaturization operation that obtains particle dispersion liquid reaches (III) drying process of dry described particle dispersion liquid.
4, the compositions that contains microgranule as claimed in claim 1, described compositions is prepared by the preparation method that comprises following operation, and promptly (I) mixes insoluble drug, surfactant and first poor solvent, obtains the mixed processes of mixed liquor; (II) use the wet type dispersion machine with described mixed liquor miniaturization, obtain the miniaturization operation of particle dispersion liquid; (III) obtain first drying process of first mixture by the described particle dispersion liquid of drying; (IV) in described first mixture, add the interpolation operation that the ring-type oligosaccharide and second poor solvent obtain second mixture; (V) second drying process of dry described second mixture.
5, as each described compositions that contains microgranule in the claim 2 to 4, wherein, mixing is dissolved in the insoluble drug solution that good solvent obtains with insoluble drug in described mixed processes.
6,, wherein, also be included in the enrichment process that described drying process or described first drying process concentrate described particle dispersion liquid before or contain the particle dispersion liquid of described ring-type oligosaccharide as each described compositions that contains microgranule in the claim 2 to 5.
7, as each described compositions that contains microgranule in the claim 2 to 6, wherein, described drying process or described first drying process are the drying processes that adopts spray drying method.
8, as each described compositions that contains microgranule in the claim 2 to 7, wherein, described wet type dispersion machine is a homogenizer.
9, as each described compositions that contains microgranule in the claim 1 to 8, it is characterized by the described surfactant of described ring-type oligosaccharide enclose.
10, as each described compositions that contains microgranule in the claim 1 to 9, wherein, described ring-type oligosaccharide is a cyclodextrin.
11, as each described compositions that contains microgranule in the claim 1 to 10, wherein, described surfactant is to have the surfactant of carbon number at the hydrocarbon chain more than 4.
12, as each described compositions that contains microgranule in the claim 1 to 11, wherein, with respect to the described compositions that contains microgranule of 100 mass parts, insoluble drug is 0.1～40 mass parts.
13, a kind of solid pharmaceutical composition, described compositions contain just like each the described compositions that contains microgranule in the claim 1 to 13.
14, solid pharmaceutical composition as claimed in claim 13, wherein, described solid pharmaceutical composition is selected from tablet, granule, capsule and dry syrup.
15, a kind of preparation of compositions method that contains microgranule, described preparation method comprises following operation, promptly (I) mixes insoluble drug, surfactant and poor solvent, obtains the mixed processes of mixed liquor; (II) use the wet type dispersion machine with described mixed liquor miniaturization, obtain the miniaturization operation of particle dispersion liquid; (III) in described particle dispersion liquid, add the interpolation operation of ring-type oligosaccharide and (IV) drying contain the drying process of the particle dispersion liquid of described ring-type oligosaccharide.
16, a kind of preparation of compositions method that contains microgranule, described preparation method comprises following operation, promptly (I) mixes insoluble drug, surfactant, poor solvent and ring-type oligosaccharide, obtains the mixed processes of mixed liquor; (II) use the wet type dispersion machine with described mixed liquor miniaturization, the miniaturization operation that obtains particle dispersion liquid reaches (III) drying process of dry described particle dispersion liquid.
17, a kind of preparation of compositions method that contains microgranule, described preparation method comprises following operation, promptly (I) mixes insoluble drug, surfactant and first poor solvent, obtains the mixed processes of mixed liquor; (II) use the wet type dispersion machine with described mixed liquor miniaturization, obtain the miniaturization operation of particle dispersion liquid; (III) obtain first drying process of first mixture by the described particle dispersion liquid of drying; (IV) in described first mixture, add the interpolation operation that the ring-type oligosaccharide and second poor solvent obtain second mixture; (V) second drying process of dry described second mixture.
18, as each described preparation of compositions method that contains microgranule in the claim 15 to 17, wherein, mixing is dissolved in the insoluble drug solution that good solvent obtains with insoluble drug in described mixed processes.
19, as each described preparation of compositions method that contains microgranule in the claim 15 to 18, wherein, also be included in the enrichment process that described drying process or described first drying process concentrate described particle dispersion liquid before or contain the particle dispersion liquid of described ring-type oligosaccharide.
20, as each described preparation of compositions method that contains microgranule in the claim 15 to 19, wherein, described drying process or described first drying process are the drying processes that adopts spray drying method.
21, as each described preparation of compositions method that contains microgranule in the claim 15 to 20, wherein, described wet type dispersion machine is a homogenizer.
22, as each described preparation of compositions method that contains microgranule in the claim 15 to 21, it is characterized by, at the described surfactant of ring-type oligosaccharide enclose described in the described interpolation operation.
23, as each described preparation of compositions method that contains microgranule in the claim 15 to 22, wherein, described ring-type oligosaccharide is a cyclodextrin.
24, as each described preparation of compositions method that contains microgranule in the claim 15 to 23, wherein, described surfactant is to have the surfactant of carbon number at the hydrocarbon chain more than 4.
25, as each described preparation of compositions method that contains microgranule in the claim 15 to 24, wherein, with respect to the described compositions that contains microgranule of 100 mass parts, insoluble drug is 0.1～40 mass parts.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004289680 | 2004-10-01 | ||
| JP289680/2004 | 2004-10-01 |
Publications (1)
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|---|---|
| CN101031285A true CN101031285A (en) | 2007-09-05 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005800332595A Pending CN101031285A (en) | 2004-10-01 | 2005-09-30 | Composition containing fine particles and process for producing the same |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US20070298111A1 (en) |
| EP (1) | EP1806129A1 (en) |
| JP (1) | JP4884975B2 (en) |
| KR (1) | KR20070057901A (en) |
| CN (1) | CN101031285A (en) |
| AU (1) | AU2005290583A1 (en) |
| CA (1) | CA2580529A1 (en) |
| IL (1) | IL181935A0 (en) |
| WO (1) | WO2006038552A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110545674A (en) * | 2018-01-12 | 2019-12-06 | 味滋康控股有限公司 | paste containing food microparticles and method for producing same |
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| EP1938842A4 (en) * | 2005-09-01 | 2013-01-09 | Eisai R&D Man Co Ltd | Method for preparation of pharmaceutical composition having improved disintegradability |
| GB0613925D0 (en) * | 2006-07-13 | 2006-08-23 | Unilever Plc | Improvements relating to nanodispersions |
| EP1923053A1 (en) * | 2006-09-27 | 2008-05-21 | Novartis AG | Pharmaceutical compositions comprising nilotinib or its salt |
| DE102008001811A1 (en) * | 2008-05-15 | 2009-11-19 | Beiersdorf Ag | Cosmetic preparations for reducing sweat odor with ABCC modulators |
| CN103314039B (en) * | 2010-12-09 | 2015-04-01 | 第一工业制药株式会社 | Method for manufacturing aqueous-dispersion composition of coumarone-indene resin, and said aqueous-dispersion composition |
| US8962650B2 (en) | 2011-04-18 | 2015-02-24 | Eisai R&D Management Co., Ltd. | Therapeutic agent for tumor |
| US9945862B2 (en) | 2011-06-03 | 2018-04-17 | Eisai R&D Management Co., Ltd. | Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds |
| US9801855B2 (en) * | 2012-03-07 | 2017-10-31 | National Institute Of Pharmaceutical Education And Research (Niper) | Nanocrystalline solid dispersion compositions and process of preparation thereof |
| KR101956586B1 (en) * | 2012-03-27 | 2019-03-11 | 일양약품주식회사 | Pharmaceutical composition and preparation method thereof |
| WO2014098232A1 (en) * | 2012-12-21 | 2014-06-26 | Yamashita Chikamasa | Pharmaceutical composition comprising pi3 kinase inhibitor, pharmaceutical composition comprising compound which acts on vitamin d receptor, freeze-dried composition, method for producing freeze-dried composition, and pharmaceutical composition for transpulmonary administration |
| JPWO2014098176A1 (en) | 2012-12-21 | 2017-01-12 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Amorphous quinoline derivative and method for producing the same |
| US10517861B2 (en) | 2013-05-14 | 2019-12-31 | Eisai R&D Management Co., Ltd. | Biomarkers for predicting and assessing responsiveness of endometrial cancer subjects to lenvatinib compounds |
| DK2896628T3 (en) * | 2014-01-20 | 2019-01-14 | Jennewein Biotechnologie Gmbh | Process for Effective Purification of Neutral Milk Oligosaccharides (HMOs) from Microbial Fermentation |
| KR102329681B1 (en) | 2014-08-28 | 2021-11-23 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | High-purity quinoline derivative and method for manufacturing same |
| DK3263106T3 (en) | 2015-02-25 | 2024-01-08 | Eisai R&D Man Co Ltd | PROCESS FOR SUPPRESSING BITTERNESS OF QUINOLINE DERIVATIVES |
| WO2016140717A1 (en) | 2015-03-04 | 2016-09-09 | Merck Sharp & Dohme Corp. | Combination of a pd-1 antagonist and a vegfr/fgfr/ret tyrosine kinase inhibitor for treating cancer |
| JP6757959B2 (en) | 2015-06-16 | 2020-09-23 | 株式会社 ＰＲＩＳＭ ＢｉｏＬａｂ | Anti-cancer agent |
| CN105256649A (en) * | 2015-09-11 | 2016-01-20 | 句容市兴武包装有限公司 | Moistureproof agent for paper products and preparation method therefor |
| CN108210501B (en) * | 2016-12-14 | 2019-03-08 | 中国人民解放军军事医学科学院毒物药物研究所 | A kind of medicinal composition for injections of sulfonylureas and preparation method thereof |
| CN112972390B (en) * | 2021-03-02 | 2022-09-16 | 天津大学 | L-menthol indometacin-loaded composite particle and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2692168B1 (en) * | 1992-06-16 | 1995-03-24 | Centre Nat Rech Scient | Preparation and use of new dispersible colloidal systems based on cyclodextrin, in the form of nanospheres. |
| US5576311A (en) * | 1994-11-30 | 1996-11-19 | Pharmos Corporation | Cyclodextrins as suspending agents for pharmaceutical suspensions |
| FR2775435B1 (en) * | 1998-02-27 | 2000-05-26 | Bioalliance Pharma | NANOPARTICLES COMPRISING AT LEAST ONE POLYMER AND AT LEAST ONE COMPOUND CAPABLE OF COMPLEXING ONE OR MORE ACTIVE INGREDIENTS |
| US6555139B2 (en) * | 1999-06-28 | 2003-04-29 | Wockhardt Europe Limited | Preparation of micron-size pharmaceutical particles by microfluidization |
| ATE297196T1 (en) * | 1999-12-20 | 2005-06-15 | Nicholas J Kerkhof | METHOD FOR PRODUCING NANOMETER PARTICLES BY FLUID BED SPRAY DRYING |
| US6464988B1 (en) * | 2001-05-09 | 2002-10-15 | Usv Limited | Glipizide-cyclodextrin inclusion complexes and their pharmaceutical composition |
| AU2002364701B8 (en) * | 2001-11-20 | 2006-06-22 | Alkermes, Inc. | Compositions for sustained action product delivery |
| FR2841137B1 (en) * | 2002-06-20 | 2004-08-13 | Bioalliance Pharma | VECTORIZATION SYSTEM COMPRISING HOMOGENEOUS SIZE NANOPARTICLES OF AT LEAST ONE POLYMER AND AT LEAST ONE POSITIVELY CHARGED POLYSACCHARIDE |
| CA2495899A1 (en) * | 2002-08-15 | 2004-03-18 | Yunqing Liu | Solid nano pharmaceutical formulation and preparation method thereof |
| US7893040B2 (en) * | 2005-07-22 | 2011-02-22 | Oculis Ehf | Cyclodextrin nanotechnology for ophthalmic drug delivery |
-
2005
- 2005-09-30 KR KR1020077007431A patent/KR20070057901A/en not_active Application Discontinuation
- 2005-09-30 WO PCT/JP2005/018099 patent/WO2006038552A1/en active Application Filing
- 2005-09-30 CN CNA2005800332595A patent/CN101031285A/en active Pending
- 2005-09-30 EP EP05787703A patent/EP1806129A1/en not_active Withdrawn
- 2005-09-30 CA CA002580529A patent/CA2580529A1/en not_active Abandoned
- 2005-09-30 JP JP2006539262A patent/JP4884975B2/en not_active Expired - Fee Related
- 2005-09-30 AU AU2005290583A patent/AU2005290583A1/en not_active Abandoned
- 2005-09-30 US US11/664,217 patent/US20070298111A1/en not_active Abandoned
-
2007
- 2007-03-14 IL IL181935A patent/IL181935A0/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110545674A (en) * | 2018-01-12 | 2019-12-06 | 味滋康控股有限公司 | paste containing food microparticles and method for producing same |
| CN110545674B (en) * | 2018-01-12 | 2021-07-16 | 味滋康控股有限公司 | Paste containing food microparticles and method for producing same |
Also Published As
| Publication number | Publication date |
|---|---|
| JP4884975B2 (en) | 2012-02-29 |
| EP1806129A1 (en) | 2007-07-11 |
| KR20070057901A (en) | 2007-06-07 |
| AU2005290583A1 (en) | 2006-04-13 |
| US20070298111A1 (en) | 2007-12-27 |
| CA2580529A1 (en) | 2006-04-13 |
| IL181935A0 (en) | 2007-07-04 |
| JPWO2006038552A1 (en) | 2008-05-15 |
| WO2006038552A1 (en) | 2006-04-13 |
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